Zucker fatty rats lost nearly 20% of their body weight in two weeks while receiving the drug, which increases brain levels of gamma-aminobutyric acid (GABA), reported Stephen L. Dewey, Ph.D., of Brookhaven National Laboratory, and colleagues in the September issue of Synapse.

The drug, known as well as gamma-vinyl-GABA, also caused adolescent Zucker rats as well as normal rats to gain significantly less weight than untreated animals after 40 days, the researchers said.

"[Vigabatrin] may be useful as a treatment for obesity," Dr. Dewey and colleagues said. "That these results occurred in genetically obese animals offers the possibility that [vigabatrin] may even help manage severe obesity resulting from binge eating."

The agent is now under FDA review as a treatment for complex partial seizures and infantile spasm. It has been marketed for these indications in Europe and elsewhere for many years. FDA concerns about visual side effects have led to withdrawals of previous marketing applications.

Dr. Dewey said that the rationale for this drug in obesity is its indirect effect on dopamine pathways.

Previous studies in his lab and elsewhere have found that, by increasing brain GABA levels, vigabatrin inhibits dopamine release in response to environmental stimuli.

Drugs and behaviors that give pleasure to humans provoke dopamine release, inhibition of which also reduces the enjoyable sensation.

Dr. Dewey had found earlier that vigabatrin reduced cocaine and methamphetamine use by animals. Two separate companies are now sponsoring clinical trials with vigabatrin as a treatment for addiction to these drugs.

Because the pleasure associated with food is also mediated by dopamine, Dr. Dewey said it made sense to test vigabatrin's effects on eating behaviors and body weight in animal models.

The rats could eat as much as they wanted at any time in all the experiments.

Mean weights in six adult Zucker rates dropped to 360 g after 14 days of treatment, from 440 g at baseline (Pâ‰¤0.006).

Within five days after stopping the drug, mean weights increased to about 415 g, the researchers reported.

Adolescent Zucker rats not receiving vigabatrin went from about 200 g at baseline to 475 g after 40 days. In contrast, animals treated with 300 mg/kg of the drug weighed about 305 g on average at day 40 (P<0.05).

Animals receiving the drug at 150 mg/kg also gained significantly less weight than untreated rats, but by a much smaller margin.

Another study in normal adolescent Sprague-Dawley rats also found significantly less weight gain with vigabatrin: from a mean baseline weight of about 115 g, untreated animals reached nearly 365 g at day 40, compared with about 260 g in those receiving vigabatrin.

In all three experiments, the differences in weight correlated significantly with food intake, with r values of 0.4 to 0.5 (P<0.001).

Dr. Dewey said ongoing follow-up studies indicated the effects on weight loss were durable, with 25% weight losses in Zucker rats maintained for as long as a year.

He said the effects on eating appeared to be two-fold: it depressed the animals' interest in food and made them feel sated sooner when they did eat, compared with untreated rats.

But whether vigabatrin has the same effects in humans remains to be seen.

The clinical experience with the drug contains little evidence that it will.

Appetite loss or weight loss have not been commonly reported in patients receiving vigabatrin as an anticonvulsant. And Dr. Dewey acknowledged that cocaine and methamphetamine addicts tend to gain weight on vigabatrin.

He said the latter group tends to be underweight to begin with and have disturbed dopamine responses, such that the drug's effects may be different than in those with normal or excess weight.

And patients with epilepsy have numerous abnormalities in brain neurotransmitters, perhaps causing them to react differently to vigabatrin than others would, Dr. Dewey offered.

On the basis of the drug's biological effects and the rat studies, he said the drug could be particularly effective against binge eating, perhaps the most difficult eating disorder to treat.

Reports from clinical trials of the drug in cocaine addiction, which used lower doses than are typical for seizure treatment, showed no evidence of visual disturbances.

The research was funded by the Department of Energy and the National Institute on Drug Abuse. Dr. Dewey is named on patents related to vigabatrin. No other potential conflicts of interest were reported.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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